KR870001440B1 - Process for preparing cephalosporin compound - Google Patents

Abstract

Compds. of formula (I) and their salts are new (where R1 is H or lower alkyl; R2 is (1-methyl-1H-tetrazol-5-yl)thio; R3 is COOH; n is 2 or 3, or R2 is Y-substd. pyridinio and R3 is COO-; Y is H, CH2OH or CONH2). (I) have antibacterial activity, often higher than that of cefmenoxime and ceftazidime against Gram-negative and Gram-positive bacteria, and may be used as medicaments or animal feed bacteria.

Description

[Name of invention]

Process for preparing cephalosporin compound

Detailed description of the invention

The present invention relates to a novel cephalosporin compound and a method for preparing the same. In particular, the present invention relates to compounds of the general formula (I) and pharmaceutically acceptable salts thereof.

의 기, R³는 -COO-이고, 또 Y는 수소, 히드록시메틸 또는 카르밤오일 ; n은 2의 정수이다.In the above, R ¹ is hydrogen or lower alkyl; R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio, R ³ is carboxy, n is an integer of 2 or 3, or R ² is a general formula

, R ³ is -COO-, and Y is hydrogen, hydroxymethyl or carbamoyl; n is an integer of 2.

Also provided according to the invention is a pharmaceutical composition comprising cephalosporin compound (I) or a salt thereof as an active ingredient and an inert carrier thereof and used as an antimicrobial agent.

The new cephalosporin compound (I) and pharmaceutical salts thereof of the present invention exhibit potent antimicrobial activity against a wide variety of microorganisms, including gram positive and gram negative bacteria, and are caused by the gram positive and gram negative bacteria described above. It is useful as a chemotherapeutic agent for ondol, including nutritional supplements for animal feed, or antibacterial agents in the treatment of infectious diseases.

의 기, R³가 -COO-이며, Y가 수소, 히드록시메틸 또는 카르밤오일, n이 2의 정수인 일반식(I)의 화합물들을 포함한다.Preferred subspecies of the compounds of the invention are those in which R ¹ is hydrogen or methyl, or lower alkyl R ² such as propyl is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio, and R ³ is carboxy, n Is an integer of 2 or 3; Or R ² is general formula;

Wherein R ³ is -COO-, Y is hydrogen, hydroxymethyl or carbamoyl, n is an integer of 2 and includes compounds of the general formula (I).

의 기, R³가 -COO-이고, 또 Y가 수소, 4-히드록시메틸, 3-히드록시메틸 또는 4-카르밤오일 ; 또 n이 2 또는 3의 정수인 일반식(I)의 화합물들을 포함한다.More preferred subgenus is that R ¹ is hydrogen or methyl, R ² (1-methyl-1H-tetrazol-5-yl) thio, and R ³ is carboxy; Or R ² is of the general formula

R <^3> is -COO-, and Y is hydrogen, 4-hydroxymethyl, 3-hydroxymethyl, or 4-carbamoyl; And compounds of formula (I) wherein n is an integer of 2 or 3.

의 기, R³가 -COO-, Y가 수소 또 n이 2의 정수인 일반식(I)의 화합물들이다.Particularly preferred subgenus is that R ¹ is hydrogen, R ² is

Are compounds of formula (I) wherein R ³ is -COO-, Y is hydrogen and n is an integer of 2.

의 기, R³가 COO-, Y가 수소 또 n이 2의 정수인 일반식(I) 화합물의 좌선이성체이다. 부가해서 앞에서 도시한 일반식(I)은 옥시이미노기의 이성체 배열이 Z(즉, syn-) 배열임을 표시하려는 의도를 갖고 있다.Most preferable compounds are those in which R ¹ is hydrogen and R ² is a general formula;

R ³ is COO-, Y is hydrogen and n is an enantiomer of General Formula (I). In addition, the general formula (I) shown above is intended to indicate that the isomeric arrangement of the oxyimino group is the Z (ie syn-) configuration.

Although the aforementioned Z (ie syn-) isomers of the present invention are preferred and exhibit the best biological properties, small amounts of E (or auti) isomers may also coexist due to the isomerization reaction during the chemical preparation of these compounds. have.

According to the present invention, the cephalosporin compound (I) condenses a compound of formula (II) or a reaction derivative thereof with a compound of formula (III) or a salt thereof to prepare a compound of formula (IV) And by removing the protecting group or groups therefrom.

(Y는 앞에서 정의한 바와 같다)의 기인 경우에는 -COO-이고, 또 R¹및 n은 앞에서 정의한 바와 같다.In the above, R ⁴ is a protecting group, R ⁵ is carboxy or protective carboxy when R ² is acetoxy or (1-methyl-1H-tetrazol-5-yl) thio; Or R ⁵ is R ² is a general formula;

(Y is as defined above), -COO-, and R ¹ and n are as defined above.

In the above reactions, a wide variety of protecting groups which are usually used to protect amino groups in peptide synthesis can be used as protecting group R ³ . Examples of such protecting groups include lower alkanes such as formyl, acetyl and pival oils; Mono-, di- or trihalogeno-lower alkanoils such as chloroacetyl and trifluoroacetyl; Lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; Substituted or unsubstituted benzyloxycarbonyl such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl; substituted or unsubstituted phenyl-lower alkyl such as p-methoxybenzyl and 3,4-dimethoxy-benzyl; And di- or triphenylloweralkyl such as benzohydryl and trityl. On the other hand, when R ⁵ of compound (III) or (IV) is a protective carboxy, the protecting group on the carboxyl group should be one that can be easily removed by conventional methods such as hydrolysis, acid treatment or reduction.

Examples of such protecting groups include methyl or lower alkyl such as tert-butyl; Substituted or unsubstituted phenyl-loweralkyl such as benzyl, p-methoxybenzyl and p-nitrobenzyl; Benzohydryl; Tri-lower alkylsilyls such as trimethylsilyl and the like.

When R ⁵ is carboxy, it is preferable to convert compound (III) to a salt before proceeding with the condensation reaction.

Suitable examples of compound (III), salts include inorganic salts such as sodium, potassium salts or organic salts such as trimethylamine, trimethylamine salts.

In particular, although compound (II) may exist in two optical isomeric forms due to the asymmetric carbon atom contained in the group of the following general formula (IX-a) ( ^* denotes an asymmetric carbon atom), Isomers or racemic variants thereof can all be used for the purposes of the present invention.

Throughout the specification and claims, the "left isomers" of compounds (I), (II) or (IV), wherein R ¹ is hydrogen and n is an integer of 2, the absolute arrangement at the asymmetric carbon atom of the aforementioned compounds is S -Array and "priority isomer" means that the absolute configuration at the asymmetric carbon atom of the aforementioned compound is R-array.

The condensation reaction of Compound (II) or a reaction derivative thereof with Compound (III) or a salt thereof may be carried out by a conventional method.

For example, the condensation of the compound (II) and the compound (III) in free form is carried out in a solvent in the presence of a dehydrating agent.

Examples of suitable dehydrating agents are dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinocarbodiimide N-ethyl-N- (3-dimethylaminopropyl) -carbodiimide, phosphorus oxychloride, thionyl chloride Oxalyl chloride, triphenylphosphine and analogs thereof.

Vilsmeier reagents prepared from dimethylformamide and phosphorus oxychloride, from dimethylformamide and oxalyl chloride, from dimethylformamide and phosgene, or from dimethylformamide and thionyl chloride can also be used as the above dehydrating agents. Can be. This reaction is preferably carried out at a temperature of -50 to 50 ° C, in particular at -30 to 20 ° C.

Dioxane, terahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, N, N-dimethylacetamide, ethyl vinegar acetate, pyridine, acetone, water and the like are suitable as solvents.

On the other hand, the condensation reaction of the reaction derivative of compound (II) with compound (III) or a salt thereof can proceed together in a solvent with or without an acid acceptor.

Examples of suitable reaction derivatives of compound (II) include the corresponding acid halides (e.g. chlorides, bromide), mixed anhydrides (e.g. mixed anhydrides of alkyl carbonates and compound (II)), active esters (e.g. p-nitrophenyl Esters, 2, 4-dinitrophenyl esters, succinimide esters, praralamide esters, benzotriazole esters, 2-pyrrolidin-1-yl esters, acid azides and acid amides (e.g., imidazoleamides, 4-substituted-imidazoleamides, triazoleamides).

Dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, N, N-dimethylacetamide, ethyl vinegar acetate, pyridine, acetone and water are suitable as solvents.

Particularly suitable examples of acid acceptors described above include alkali metal hydroxides (eg potassium hydroxide, sodium hydroxide), alkali metal carbonates or bicarbonates (eg sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate), trialkylamines (eg trimethylamine) , Triethylamine), N, N-dialkylaniline (e.g., N, N-dimethylaniline, N, N-diethylaniline), pyridine and N-alkyl-morpholine (e.g., N-methylmorpholine) Included.

The reaction is preferably carried out at a temperature of -50 to 50 ° C, in particular -30 to 20 ° C.

Removal of protecting groups or groups from the compound (IV) thus obtained can be carried out by conventional methods such as, for example, hydrolysis, solvolysis, acid treatment or reduction.

For example, when the protecting group R ⁴ is formyl, acetyl tert-butoxycarbonyl, benzohydryl or trityl and the protecting group on the carboxyl group is tert-butyl or benzohydryl, the above-mentioned groups or groups are compound (IV). ) Can be removed by treating with acid.

Suitable examples of such acids include, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluene-sulfonic acid, hydrochloric acid or hydrogen bromide, in particular trifluoroacetic acid.

This reaction can be run in the presence or absence of a solvent. Examples of the solvent include water, methanol, ethanol, vinegar acid or dioxane. It is preferred to proceed with the reaction at a temperature of -30 to 70 ° C, in particular 0 to 30 ° C. In particular, when trifluoro vinegar acid is used as the acid, it is preferable to react in the presence of anisel. The protecting group R ⁴ is benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzyl, p-methoxy-benzyl or 3,4-dimethoxybenzyl, and the protecting group on the carboxyl group is benzyl, p-methoxybenzyl or p In the case of nitrobenzyl, the above-mentioned removal of the protecting group or groups can proceed by catalytic hydrogenation of compound (IV) in hydrogen gas in the presence of a catalyst. The catalytic hydrogenation reaction is preferably carried out at temperatures of 0 to 100 ° C., in particular 10 to 40 ° C. under atmospheric pressure or pressure.

Preferred examples of the catalyst include palladium-BaCO ₃ , palladium-charcoal and palladium-black. Methanol, ethanol, tetrahydrofuran and water are suitable as reaction solvents. In particular when the protecting group R ⁴ is trifluoroacetyl, pivaloyl methylcycarbonyl or ethyl, the aforementioned groups or groups can be removed by hydrolysis of compound (IV). The hydrolysis of compound (IV) can be advanced by conventional methods, for example by treatment with an alkali agent such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or bromic acid. The above hydrolysis is preferably carried out at a temperature of from 0 to 70 ° C, in particular from 10 to 30 ° C. When the protecting group R ⁴ is chloroacetyl, the aforementioned groups can be removed by treating compound (IV) with thiourea in a solvent. Methanol, ethanol and water are suitable as solvents. The reaction is preferably carried out at a temperature of 20 to 80 ° C, in particular 40 to 80 ° C.

The starting compound (II) of the present invention reacts, for example, a compound of the following general formula (VI) with a compound of the following general formula (IX) at a temperature of 10 to 50 ° C. in a solvent such as dimethyl sulfoxide in the presence of an alkaline agent such as potassium carbonate. It can be prepared by preparing a compound of formula (VII) and then hydrolyzing it.

In the above, X is halogen, R ¹ , R ⁴ and n are as defined above. In contrast, starting compound (II) hydrolyzes compound (VI) to prepare a compound of formula (VIII), which is then dissolved in a solvent such as dimethyl sulfoxide at a temperature of 10 to 40 ° C. in the presence of an acid acceptor such as sodium hydride. It may also be prepared by reacting with a compound of formula (IX).

Wherein X is halogen, R ¹ , n and X are as defined above.

In addition, as described above, compound (II) contains two optical isomers due to the asymmetric carbon contained in the group of the general formula (IX-a) (in the following formula, the ^asterisk denotes an asymmetric carbon atom).

However, if necessary, these optical isomers can be separated into individual optical isomers by optical separation.

For example, compound (II) wherein R ¹ is hydrogen, n is an integer of 2 and R ⁴ is drithyl is L- or D in coagulating racemic variant of compound (II) (e.g., a mixture of methanol and dioxane). By reacting with -phenylalanine methyl ester to prepare these diastereomer salts, these diastereomers can be separated into their respective components using selective recrystallization and can be easily separated into their respective optical isomers.

According to the selective recrystallization method described above, the minimum soluble diastereomer is recovered from the reaction mixture, and the more soluble diastereomer is dissolved in the solution and remains.

The above-mentioned selective crystallization operation is preferably carried out at a temperature of 10 to 40 ℃.

The cephalosporin compound (I) and pharmaceutically acceptable salts thereof of the present invention are streptococci (eg, St. faecalis, St. pneumoniae), staphylococci (eg, staphylococci) Reus (S. aureus), Staphylococcus epiderimides (S. epider)

midis) and Pseudomonas [eg Pseudomonas aruginosa, Pseudomonas putida, Pseudomonas stutzeari], a wide variety of microorganisms, including microorganisms belonging to the genus It shows strong antimicrobial activity against, and especially strong antimicrobial action against both gram positive and gram negative bacteria.

For example, 7β {(Z) -2- (2-aminothiazol-4-yl) -2 [(2-pyrrolidone-3-yl) oxyamino] ashetamido} -3- (1-pyri Diniomethyl) -3-cepem-4-carboxylate (I-isomer) and 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(1-methyl-2 -Pyrrolidone-3-yl) oxyaminoacetamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid is Streptococcus paecalis CN478 Inhibitory concentration (MIC) of 12.5 and 25 ㎍ / ml (agar dilution method, incubation for 20 hours at 37 ℃, whereas the above-mentioned Cefenoxime [chemical name, 7β- [ (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyaminoacetamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]- 3-Cefem-4-carboxylic acid] and Ceftazidime (chemical name: 7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2) -Yloxyamino) acetamido] -3- (1-pytidiniomethyl] -3-ceedi-4-carboxylay ] Of M.I.C was more than 100㎍ / ml.

7β {(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido] against Staphylococcus aureus 252R The antimicrobial activity of 3-[(1-methyl-1H-tetrazol-5-yl) thio-methyl] -3-cepem-4-carboxylic acid is also 16 times more potent than the activity of cefenmenoxime and ceftazidime. . In addition, compounds (I) and salts thereof include bacillus (eg Bacillus subtilis), Escherichia (eg Escherichia coli), Klebsiella (eg K. pneumococcus), Enterobacter [ For example, it exhibits potent antimicrobial activity against bacteria belonging to the genus Entrobacter aerogenes, E. cloacae and Serratia (eg erythrocytes).

The cephalosporin compound (I) exhibits strong antimicrobial activity against other bacteria belonging to the genus Citrobacter, Proreus, Shigella, Haemophilus and Salmonella.

In addition, cephalosporin compound (I) and its salts are resistant to microbial infections of various bacteria, including both Staphylococcus aureus and Pseudomonas aeruginosa, due to their high absorption or permanent therapeutic effects in living tissues. It has a strong protective effect: β-lactamase production. It has high stability against various microorganisms, especially β-lactamase produced by Proteus vulgaris. Is characteristic.

Esculde, 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyamino] acetamido} -3- (1 No mice died after subcutaneous administration of -pyridiniomethyl) -3-cepem-4-carboxylate (I-isomer) to SD-males at a dose of 1000 mg / kg for 14 consecutive days.

The cephalosporin compound (I) of the present invention can be used in pharmaceutical form in both free and salt form.

Salts of pharmaceutically acceptable compounds (I) are, for example, non-toxic metal salts such as sodium, potassium or aluminum salts: ammonium salts: salts with non-toxic amines such as trialkalamines (eg triethylamine and procaine) Salts with inorganic acids such as hydrochloric acid or bromic acid; salts with organic acids such as oxalic acid or tartaric acid. These salts can be easily obtained by treating with stoichiometrically the same molar amount of the corresponding alkali agent or acid in an aqueous solvent containing the compound (I). The cephalosporin compound (I) and salts thereof can be administered orally or by injection (eg, intravenously, intramuscularly, subcutaneously). The daily dosage of compound (I) or salts thereof may vary widely depending on the age, weight or condition of the patient to be treated, and the severity of the disease.

Generally, however, the preferred daily dosage of the aforementioned compound (I) or salts thereof is from about 0.002 to about 0.2 in particular 0.01 to 0.04 g per kilogram of body weight per day.

Compound (I) or salts thereof may also be used in pharmaceutical formulations containing the aforementioned compounds in combination or mixed with pharmaceutical excipients suitable for oral or injectable administration. Suitable excipients include, for example, gelatin, lactose, glucose, sodium chloride, starch, stearin magnesium, talcum, vegetable oils and other known pharmaceutical excipients.

The pharmaceutical preparation may be in the form of a solid such as tablets, coated tablets, pills or gapsouls, or in liquid form such as solution suspensions or emulsions. These agents may be sterilized and or in addition contain adjuvant such as stabilizers, wetting agents or emulsifiers.

Practical and preferred embodiments of the present invention have been described in the following examples. The term "lower alkyl" in this specification and in the claims means alkyl having 1 to 4 carbon atoms.

[Experiment I]

(Antimicrobial activity in vitro)

The minimum inhibitory concentration (M.I.C. μg / ml) of the test compound was measured by the standard agar plate dilution method (based on the Japanese Chemical Therapy Society's standard method). The medium used in these experiments was Muel

ler-Hinton agar (MHA: Nissui). The test results are listed in the following table.

[Table 1]

Note: 1) 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) jade

Camino] acetamido} -3- (1-pyridiniomethyl) -3-cepem-4-carboxylate (I-

Isomers)

2) Chemical name = 7β-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyamino) ace

Thiamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid

3) Chemical name = 7β-[(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxy-pro

P-2-yloxyimino) acetamido] 3- (1-pyridiniomethyl) -3-cedim-4-carboxylate.

[Experiment II]

Protective effect against bacterial infection in mice

Ten male mice weighing 20 ± 1 g were used at individual dose levels. Sufficient bacteria were administered to the mice intraperitoneally to kill all untreated mice within 24 hours.

All bacteria were suspended in 6% mucin. Test compounds were administered intramuscularly 1 hour after infection.

Survival was measured 7 days after infection. Average effective dose of test compound (ED ₅₀ , mg / k

g) was determined by probit analysis.

The test results are listed in the following table along with the M.I.C (µg / ml) of the test compounds, which were estimated by the same method as described in Experiment I.

[Table 2]

Note: Figures in parentheses indicate the M.I.C (minimum inhibitory concentration, μg / ml) of each test compound.

1) -3); Same as each state mark in the first table.

Example 1

(1) 3.2 g of (Z) -2- (2-tritylaminothiazol-4-yl-2-[(2-pyrrolidone-3-yl) oxyamino] acetic acid was added to 60 ml of tetrahydrofuran. Suspension and thereto are added 2.05 g of tert-butyl 7-aminocephalosporanate, 1.:27 g of 1-hydroxybenzotriazole and 1.93 g of dicyclohexylcarbodimide.

The mixture is stirred for 3 hours at room temperature. Insoluble matters are filtered off and the filtrate is lyophilized under reduced pressure.

The residue is dissolved in ethyl acetate and the solution is washed successively with 1% hydrochloric acid, 5% aqueous sodium bicarbonate solution and water. The ethyl acetate solution is concentrated to dryness under reduced pressure. The residue thus obtained is then purified by silica gel chromatography (solvent, chloroform: methanol: 98.5: 1.5). 4.3 g tert-butyl 7β-{(Z) -2- (2-tritylaminothiazol-4-yl-2-[(2-pyrrolidone-3-yl) oxyamino] acetamido} Cephalosporanate is obtained as a pale yellow powder Melting point 135-145 ° C. (decomposition), NMR (CDCl ₃ ) δ: 1.52 (9H8 s), 2.02 (3H, s), 2.2-2.7 (2H, m), 3.0-3.5 (4H, m), 4.5-5.3 (4H, m), 5.6-6.0 (1H, m), 6.70 (1H, s), 6.9-7.5 (17H, m), 8.4-8.78 (1H, wide ).

(2) 1.0 g tert-butyl 7β-{(Z) -2- (2-trityl aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acet Amido} cephalosporanacetrool is added to a mixture of 20 ml trifluoroacetic acid and 1 ml of anisole and the mixture is stirred at room temperature for 20 minutes. The mixture is concentrated under reduced pressure to remove trifluoroacetic acid. Ether is added to the residue and the resulting powder is recovered by filtration.

The powder is suspended in 10 ml of water, and sodium bicarbonate is added thereto to dissolve the powder described above. The solution was washed with ethyl acetate and chromatographic separation was performed with resin Amberlite XAD-2 (manufactured by Rohm & Haas, USA) with a nonionic polymer using water as eluent.

Fractions containing the cephalosporin compound are recovered and concentrated under reduced pressure to remove the solvent. Acetone is then added to the obtained residue and the resulting powder is recovered by filtration.

320 mg of sodium 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} cephalosporanate Obtained as a colorless powder.

NMR (D ₂ O) δ: 2.10 (3H, s), 2.2-2.7 (2H, m), 3.15-3.85 (4H, m), 4.6-5.00 (2H, m), 5.01 (1H, t, J = 7 Hz), 5.16 (1H, d, J = 5 Hz), 5.77 (1H, d, J = 5 Hz), 6.98 (1H, s).

Example 2

(1) 4.0 g of (Z) -2- (2-tritylaminothiazol-4-yl-2-[(2-pyrrolidone-3-

I) oxyamino] acetic acid was dissolved in a mixture of 30 ml of tetrahydrofuran and 10 ml N, N-dimethylacetamide, and 1.27 g of 1-hydroxybenzotriazole and 1.93 g of dicyclohexylcarbodiamide were added thereto. Add. The mixture was stirred at 0-5 [deg.] C. for 2 hours and then the mixture was mixed with 30 ml of N, N-dimethylacetamide-water containing 2.12 g of 7-aminocephalosporanic acid and 4 g of triethylamine (water content: 15%). The addition is carried out under ice cooling. This mixture is then stirred at the same temperature for 1.5 hours. The reactive material is filtered off and the filtrate is concentrated under reduced pressure to remove the solvent. Inject the residue into 300 ml of water. The mixture was adjusted to pH8 with sodium bicarbonate, washed with ethyl acetate, adjusted to PH3 with 2N hydrochloric acid, and extracted with ethyl acetate. The extract is dried and concentrated to dryness under reduced pressure.

Ether is added to the residue thus obtained and the resulting powder is filtered. 3.1 g of 7β-{(Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} cephalospo Obtain lanic acid.

NMR pDMSO-d ₆ ): 2.03 (3H, s), 2.1-2.5 (2H, m), 3.0-3.7 (4H, m), 4.4-5.2 (4H, m), 5.5-5.2 (4H, m), 5.5-5.9 (1H, m), 6.71 (1H, s), 7.0-7.6 (15H, m), 7.84 (1H, s), 8.80 (1H, wide s), 9.50 (1H, wide d).

(2) 40 ml of 80% aqueous formic acid was added 3.0 g of 7β- (Z)-(2)-(2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidin-3-yl ) Oxyimino] acetamido} -cephalosporanic acid and the mixture is stirred for 2 hours at room temperature. Insoluble matter is filtered off, and the filtrate is concentrated to dryness under reduced pressure.

Water is added to the residue and the aqueous mixture is neutralized with sodium bicarbonate and washed with ether.

This aqueous mixture is then subjected to column chromatography separation of nonionic polymer resin Diaion Hp-20 (registered trademark, manufactured by Mitsubishi Chemical Co., Ltd., Japan) using water as the eluent. Fractions containing the cephalosporin compound were recovered and concentrated to dryness under reduced pressure to yield 1.5 g of sodium 7β-{(Z) -2- (2-aminotazol-4-yl) -2-[(2-pyrroli). Don-3-yl) oxyimino] acetamino} -cephalosporanate is obtained.

The physical and chemical properties of this product are the same as those of the sample obtained in Example I- (2).

Example 3

(1) 200 ml of tetrahydrofuran with 3.25 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid Dissolved in and added thereto was 3.14 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylate, 1.03 g 1-hydroxybenzotriazole and 1.57 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 2 hours at room temperature.

The insoluble matter is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in acetic acid broad and washed successively with 1% hydrochloric acid, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution.

The ethyl acetate solution is then dried and concentrated to dryness under reduced pressure. The residue thus obtained was purified by silica gel chromatography (solvent, ethyl acetate: benzene = 5: 2) to obtain 3.7 g of benzhydryl 7β-{(Z) -2- (2-tritylaminoriazol-4-yl. ) -2 [(2-pyrrolidone-3-yl) oxyimino] acetamino} -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-car Obtain a carboxylate.

Welding 122-126 ° C (decomposition).

NMR (CDCl ₃ ) δ: 2.2-2.7 (2H, m), 3.0-3.5 (2H, m), 3.6-3.75 (2H, m), 3.78 (3H, s), 4.2-4 .-) 2H, m ), 5.03 (2H, m), 5.7-6.05 (1H, m), 6.75 (1H, s), 6.88 (1H, s), 7.1-7.5 (27H, m), 8.80 (1H, wide).

(2) 860 g of benzhydryl 7β-{(Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyamino] acetami FIG.}-3-[) 1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylate is added to a mixture of 10 ml trifluoroacetic acid and 0.5 ml anisole, and The mixture is stirred for 20 minutes at room temperature. The mixture is concentrated under reduced pressure to remove trifluoroacetic acid.

Ether is added to this residue and the powder obtained is collected by filtration. This powder is suspended in water and sodium bicarbonate is added to dissolve the powder.

This solution is washed with ethyl vinegar and chromatographed separation of the nonionic polymer resin Amberlite XAD-2 (registered trademark, Rojm & Haas, USA) using water as eluent. Fractions containing the cephalosporin compound were recovered and concentrated to dryness under reduced pressure to yield 0.3 g of sodium 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrroli). Don-3-yl) oxyimino] acetamino} -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefe-4-carboxylate is obtained.

NMR (DMSO-d ₆ ) δ: 2.1-2.5 (2H, m), 3.1-3.5 (2H, m), 3.94 (3H, s), 4.2-4.5 (2H, m), 4.6-4.8 (1H, m ), 5.30 (1H, d, J = 5 Hz), 5.5-5.8 (1H, m), 6.76 (1H, s), 7.3 (2H, teal s), 8.00 (1H, s), 9.55 (1H, wide ).

Example 4

0.57 g of oxalyl chloride is added to 15 ml of chloroform containing 0.35 g of dimethylformamide at a temperature of −5 to 0 ° C. and the mixture is stirred at the same temperature for 15 minutes.

1.54 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid, 0.3 g triethylamine and 15 ml chloroform Is added to the above-mentioned mixture at a temperature of -30 to -35 ° C, and the mixture is stirred again at the same temperature for 5 minutes.

Then a 7β-amino-3- (1-pyridinio-methyl) -3-cepem-carboxylate solution dissolved in chloroform (this solution was suspended in 10 ml chloroform and 1.82 g of the dihydrochloride of cefem compound described above. To this, 4 ml of N, O-bis (trimethylsilyl) acetamide is added to dissolve the salt described above) is added to the compound described above at a temperature of -35 to -30 ° C and the mixture is kept at the same temperature for 10 minutes. Stir at a temperature of from 1 to 30 to -10 ° C. The mixture is concentrated to dryness under reduced pressure. 60 ml of 80% aqueous formic acid is added to the residue, and the aqueous mixture is stirred at room temperature for 1 hour. 50 ml of water are added to the aqueous mixture described above.

The insoluble matter is then filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure.

The residue thus obtained is dissolved in water to perform column chromatography separation of a nonionic polymer resin Diaion HP-20 (registered trademark, manufactured by Mitsubishi Chemical Co., Ltd., Japan). The column is washed with water and then eluted with 20% methanol. Fractions containing the cephalosporin compound are recovered and concentrated to dryness under reduced pressure.

Acetone was added to the residue thus obtained, and the resultant powder was recovered to obtain 0.84 g of 7β-{(Z) -2- (2-aminotazol-4-yl) -2-[(2-pyrrolidone-3 -Yl) oxyimino] acetamido} -3- (1-pyridiniomethyl) -3-cepem-4-carboxylate is obtained.

Melting point> 250 ℃

NMR) D ₂ O) δ: 2.2-2.7 (2H, m), 3.1-3.7 (4H, m), 4.9-5.5 (4H, m), 5.80 (1H, d, J = 5H) z, 6.92 (1H , s), 7.8-9.1 (5H, m).

[α] _D ²⁰ + 13.3 ° (C = 1.0, H ₂ O)

Example 5

1.56 g of oxalyl chloride is added to 39 ml chloroform containing 0.99 ml of dimethylformamide at a temperature of −5 to 0 ° C. and the mixture is stirred at the same temperature for 15 minutes.

4.23 g of (Z) -2- (2-ritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (d-isomer) in 39 ml of chloroform A solution of 0.84 g of triethylamine is added to the above-mentioned mixture at -30 ° C. The mixture is stirred for 5 minutes at the same temperature.

Then a solution of 7β-amino-3- (1-pyridiniomethyl) -3-cepem-4-carboxylate dissolved in chloroform (this solution was suspended in 39 ml of chloroform by dissolving 5.0 g of the dihydrochloride salt of the aforementioned cefem compound). To this was added 11 ml of N, O-bis (trimethylsilyl) acetamido, prepared by dissolving the aforementioned salts), at -30 to -10 deg. The mixture is stirred at the same temperature for 30 minutes and then concentrated to dryness under reduced pressure. 100 ml of 80% aqueous formic acid is added to the residue, and the aqueous mixture is stirred at room temperature for 1 hour. 100 ml of water are added to this mixture and the insolubles are filtered off. The filtrate is washed with ethyl acetate and concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water and subjected to column chromatographic separation of Diaion HP-20 (registered trademark, manufactured by Mitsubishi Chemical Co., Ltd., Japan).

The column is washed with water and then eluted with 20% aqueous methanol. Fractions containing the cephalosporin compound are recovered and concentrated to dryness under reduced pressure.

Acetone was added to this residue, and the resulting powder was collected by filtration to obtain 2.14 g of 7β-{(Z) -2- (2-aminothiazol-4-yl) -2- {2-pyrrolidone-3- (1) oxyimino] acetamido} -3- (1-pyridiniomethyl) -3-cepem-4-carboxylate (d-isomer) is obtained. Another name for this preferential isomer is 7β {(Z) -2- (2-aminothiazol-4-yl) -2-[((3R) -2-pyrrolidone-3-yl) oxyimino] acetamino } -3- (1-pyridiniomethyl) -3-cepem-4-carboxylate.

NMR (D ₂ O) δ: 2.1-2.7 (2H, m), 3.1-3.7 (4H, m), 4.9-5.5 (4H, m), 5.79 (1H, d, J = 5 Hz), 6.92 (1H, s), 7.8-9.1 (5H, m).

[α] _D ²⁰ + 45.7 ° (C = 1, H ₂ O)

Example 7

1.81 g of oxalyl chloride is added to 45 ml chloroform containing 1.15 ml of dimethylformamide at a temperature of −5 to 0 ° C. and the mixture is stirred at the same temperature for 15 minutes.

490 g of (Z) -2- (2-dithylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (d-isomer) in 45 ml of chloroform A solution of 0.97 g of triethylamine is added to the above-mentioned mixture at -30 ° C. The mixture is stirred for 5 minutes at the same temperature. Then a solution of 7β-amino-3- (1-pyridiniomethyl) -3-cefe-4-carboxylate dissolved in chloroform (this solution suspended 5.8 g of the dihydrochloride of the aforementioned cefe compound in 45 ml of chloroform and 12.71 ml of N, O-bis (trimethylsilyl) acetamido is added thereto to dissolve the salt described above) at -30 to -10 deg.

The mixture is stirred at the same temperature for 30 minutes and then concentrated to dryness under reduced pressure. 100 ml of 80% aqueous formic acid is added to the residue, and the aqueous mixture is stirred at room temperature for 1 hour. 110 ml of water is added to this mixture and the insoluble material is filtered off. The filtrate is washed with ethyl acetate and concentrated to dryness under reduced pressure. The residue thus obtained is dissolved in water and separated by column chromatography of nonionic polymer resin Diaion HP-20 (registered trademark, manufactured by Mitsubishi Chemical Co., Ltd., Japan). The column is washed with water and then eluted with aqueous methanol.

Fractions containing the cephalosporin compound are recovered and concentrated to dryness under reduced pressure. Acetone is added to the residue and the resulting powder is collected by filtration.

2.22 g of 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} -3- (1 Pyridiniomethyl) -3-cepem-4-carboxylate (l-isomer) is obtained.

Another name for this zoster is 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[((3S) -2-pyrrolidone-3-yl) oxyimino] acet Amido} -3- (1-pyridiniomethyl) -3-cepem-4-carboxylate.

NMR (D ₂ O) δ: 2.2-2.7 (2H, m), 3.1-3.8 (4H, m), 5.05 (1H, t, J = 7 Hz), 5.28 (1H, d, J = 5 Hz), 5.36 ( 1H, d, J = 14 Hz), 5.63 (1H, d, J = 14 Hz), 5.87 (1H, d, J = 5 Hz), 6.98 (1H, s), 8.10 (2H, t, J = 7.5 Hz), 8.57 (1H, t, J = 7.5 Hz), 8.98 (1H, d, J = 7.5 Hz)

[α] _D ²⁰ + 38.0 ° (C = 1, H ₂ O)

Example 7

(1) 50 ml of 1.5 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-[(1-methyl-2-pyrrolidone-3-yl) oxyimino] acetic acid Dissolved in tetrahydrobutane and added to 1.4 g of benzhydryl 7β-amino-3- (1-methyl-1H-tetrazol-5-yl) -3-cefe-4-carboxylate, 0.6 g 1-hydroxybenzoturazole and 0.92 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 2 hours at room temperature. This reaction mixture was then treated in the same manner as described in Example 3- (1) to yield 1.58 g of benzohydryl 7β {(Z) -2- (2-tritylaminothiazol-4-yl) -2. -[(1-methyl-2-pyrrolidone-3-yl) oxyimino] acetamido} -3- (1-methyl-1H-tetrazol-5-yl) -3-cepem-4-carboxyl The rate is added to a mixture of 1.5 ml anasol and 10 ml trifluoroacetic acid and the mixture is stirred for 30 minutes at room temperature.

The mixture is concentrated under reduced pressure to remove trifluoroacetic acid. Eret is added to the residue and the resulting powder is collected by filtration. The powder is suspended in 15 ml of water, and sodium bicarbonate is added thereto to dissolve the aforementioned powder. The solution is washed with ethyl acetate and subjected to column chromatography separation of the nonionic polymer resin Amberlite XAD-2 (registered trademark, Rohm & Hass, USA) using water as eluent.

The fraction containing the cephalosporin compound was recovered and concentrated to dryness under reduced pressure to give 0.61 g of sodium 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-{(1-methyl- 2-pyrrolidone-3-yl) oxyimino] acetamido} -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylate do.

NMR (D ₂ O) δ: 2.1-2.7 (2H, m), 2.89 (3H, s), 3.2-3.8 (4H, m), 4.05 (3H, s), 4.05-4.3 (2H, m), 4.9 -5.3 (2H, m), 5.73 (1H, doublet, J = 5 Hz), 7.00 (1H, s).

Example 8

(1) Dissolve (Z) -2- (2-tritylaminothiazol-4-yl) -2 {(2-piperidone (3) yl) oxyimino] acetic acid in 10 ml of tetrahydrofuran in 0.5 g And 0.47 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylate, 0.15 g of 1 hydrate Add oxybenzotriazole and 0.24 g of dicyclohexylcarbodiimide. The mixture is stirred for 2.5 hours at room temperature.

The reaction mixture was treated in the same manner as described in Example 3- (1) to obtain 0.47 g of benzhydryl 7β-{(Z) -2- (2-tritylaminothiazol-4-yl) -2- Obtain [(2-piperidone-3-yl) oxyimino] acetamino} -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylate do.

NMR (DMSO-d ₆ ) δ: 2.00-24.5 (H, m), 3.0-3.3 (2H, m), 3.6-3.8 (2H, m), 3.8 (3H, s), 4.1-4.3 (2H, m ), 4.6-4.8 (1H, m), 4.9-5.4 (1H, m), 5.85 (1H, d, d, J = 8 Hz, J = 5 Hz), 6.71 (1H, s), 6.81 (1H, s 7.0 -7.6 (26H, m), 9.63 (1H, doublet, J = 9 Hz).

(2) 0.4 g benzhydryl 7μ-{(Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-piperidone-3-yl) oxyimino] acetami FIG.}-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cef-4-carboxylate is added to a mixture of 10 ml trifluoroacetic acid and 0.8 ml anisole, In addition, the mixture is allowed to stand at room temperature for 30 minutes. The mixture is evaporated under reduced pressure to remove trifluoroacetic acid.

Ether is added to the residue and the resulting powder is recovered by filtration. The powder is suspended in water and sodium bicarbonate is added thereto to dissolve the powder described above. The solution was washed with ethyl acetate and chromatographic separation of the nonionic polymer resin Amberlite XAD-2 (registered trademark, manufactured by Rojm & Haass, USA).

Wash the column and then elute with 10% aqueous methane. The fraction containing the cephalosporin compound was recovered and concentrated to dryness under reduced pressure to obtain 0.9 g of sodium 7μ-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-blood Ferridone-3-)-oxyimino] acetamino} -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylate is obtained.

NMR (D ₂ O) δ: 1.5-2.3 (4H, m), 3.0-3.4 (2H, m), 3.4-3.6 (2H, m), 3.90 (3H, m), 4.0-4.2 (2H, m) , 5.03 (1H, d, J = 5 Hz), 5.63 (1H, d, J = 5 Hz), 5.85 (1H, s).

Example 9

(1) 18.2 g of phosphorus oxychloride is added dropwise to 9.2 ml of dimethylformamide under ice cooling, and the mixture is stirred at a temperature of 25 to 35 DEG C for 30 minutes. After cooling to 0 ° C., 100 ml of chloroform is added to this mixture and the mixture is further cooled to -35 ° C.

20 g of (Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid in 160 ml of N, N-dimethylacetamide (l-isomer) and a solution of 5.6 ml of triethylamine are added dropwise to the mixture described above at a temperature of -35 to -25 ° C, and the mixture is stirred at room temperature for 20 minutes.

The reaction mixture was then prepared with 7-aminocephalosporanic acid (this solution was 16 g of 7-aminocephalosporanic acid: 48 g of trimethylchlorosilane, 35.6 ml of pyridine and 160 ml of N, N-dimethylacetamide). The mixture is prepared with stirring at 10-20 ° C. for 2 hours) dropwise with stirring at a temperature of −35 to −20 ° C. After stirring for 20 minutes at the same temperature, the reaction mixture is poured into 2 l of ice water and stirred vigorously. The crystal precipitates are collected by filtration, washed with water, ethyl acetate and ether and dried under vacuum.

26.5 g of 7 μ-{(Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} cephalospo Lansan (l-isomer) is obtained as a colorless powder.

NMR (DMSO-d ₆ ) δ: 2.06 (3H, s), 2.1-2.5 (2H, m), 3.1-3.4 (2H, m), 3.45 (1H, d, J = 18 Hz), 3.75 (1H, m ), 5.17 (1H, d, J = 5 Hz), 5.6- 5.9 (1H, m), 6.81 (1H, s), 7.1-7.6 (15H, m), 7.97 (1H, s) 8.88 (1H, br, s), 9.64 (1H, doublet, J = 6 Hz).

(2) 2.5 g of 7-{(Z) -2- (2-tritylamino-thiazol-4-yl) -2-[(2-pyridone-3-yl obtained from formula (1) above ) Oxyimino] acetamino} cephaloslanic acid is dissolved in 50 ml of 80% formic acid and the solution is stirred at room temperature for 1 hour. After filtering off the non-condensables, the filtrate is concentrated under reduced pressure and water is added to the residue, which is neutralized with sodium bicarbonate.

The aqueous mixture was then washed with ethyl acetate, concentrated under reduced pressure and charged into a column filled with 200 ml of nonionic adsorbent resin (Diaion HP-20). The column was washed with water and treated in the same manner as described in Example 10- (3).

1.0 g sodium 7u {(Z) -2- (2-aminothiazol-2-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} cephalosporonic acid (l-isomer) is obtained as a pale yellow powder.

Another designation of this isomer is sodium 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[((3S) -2-pyrrolidone-3-yl) oxyimino] Acetamido} is represented by cephalosporan acid.

NMR (D ₂ O) δ: 2.12 (3H, s), 2.3-2.6 (2H, m), 3.2-3.9 (4H, m), 4.75 (1H, d, J = 13 Hz), 4.95 (1H, d, J = 13Hz), 5.10 (1H, t, J = 7Hz), 5.25 (1H, d, J = 5Hz), 5.85 (1H, d, J = 5Hz), 7.08 (1H, s)

[Examples 10 to 12]

According to the same method as in the above embodiment, the following compounds may be prepared.

(10) 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} -3- (4- Carbamoyl-1-pyridiniomethyl) -3-cepem-4-carboxylate is obtained as a pale yellow powder.

Melting Point 163-15 ° D (Decomposition)

NMR) CF ₃ CO ₂ D (δ: 2.5-3.0 (2H, m), 3.5-4.0 (4H, m), 5.2-5.5 (3H, m), 5.5-5.8 (1H, m), 5.9-6.2 ( 1H, m), 7.35 (1H, s), 8.4-8.7 (2H, m), 9.1-9.4 (2H, m).

(11) 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} -3- (4- Hydroxymethyl-1-pyridiniomethyl) -3-cepem-4-carboxylate is obtained as a pale yellow powder.

Melting Point 162-184 ℃ (Decomposition)

NMR (D ₂ O) δ: 2.3-2.7 (2H, m), 3.1-3.7 (4H, m), 4.8-5.0 (2H, m), 5.03 (2H, s), 5.24 (1H, d, J = 5 Hz), 5.3-5.6 (1H, m), 5.83 (1H, d, J = 5 Hz), 6.81 (1H, s), 7.8-8.2 (2H, m), 8.6-9.0 (2H, m).

(12) 7β-{(Z) -2- (2-aminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetamido} -3-) 3 Hydroxymethyl-1-pyridiniomethyl) -3-cepem-4-carboxylate.

Melting Point 128-135 ℃ (Decomposition)

NMR (D ₂ O) δ: 2.1-2.8 (2H, m), 3.1-3.8 (4H, m), 4.86 (2H, s), 4.9-5.1 (2H, m), 5.27 (1H, d, J = 5 Hz), 5.3-5.6 (1H, m), 5.83 (1H, d, J = 5 Hz), 6.96 (1H, s), 7.7-8.2 (2H, m), 8.3-8.6 (1H, m), 8.6- 9.1, m).

Example 15 Preparation of Starting Compound;

(1) 15.8 g of ethyl (Z) -2- (2-tritylaminothizol-4-yl) -2-hydroxyiminoacetate is dissolved in 70 ml of dimethyl sulfoxide, and 5.8 g of anhydrous carbonic acid is added thereto. Potassium is added. The mixture is stirred for 20 minutes at room temperature.

6.6 g of 3-bromo-2-pyrrolidone is added to this mixture, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into 800 ml of water, and the crystal precipitate is collected by filtration and washed with water. The crystals are dissolved in chloroform, washed with water and dried.

This chloroform solution is then evaporated under reduced pressure to remove the solvent. 100 ml of ethyl acetate is added to this residue, and it is left to stand at room temperature. The crystal precipitate thus obtained was collected by filtration and dried to obtain 16.0 g of ethyl (Z) -2- (2-tritylaminothiazol-4-yl-2 [(2-pyrrolidone-3-yl) oxy. Mino] acetate is obtained, melting point 209-210 ° C.

NMR (CDCL ₃ ) δ: 1.30 (3H, t, J = 7 Hz), 2.1-2.6 (2H, m), 3.1-3.6 (2H, m), 4.34 (2H, q, J = 7 Hz), 4.90 (1H , t, J = 7 Hz), 6.53 (1H, s), 7.0-7.6 (17H, m).

16.0 g of ethyl (Z) -2- (2-tritylaminothiazol-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetate in 160 ml methanol and 30 ml 2N The mixture is added to an aqueous sodium hydroxide solution and the mixture is heated to reflux for 30 minutes. After cooling, the crystal precipitates are collected by filtration and washed with methane.

The crystals are suspended in 30 ml of water. This suspension 2N hydrochloric acid is then adjusted to pH 3 using. The crystal precipitate was collected by filtration and dried to obtain 11.4 g (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetine. Obtain an acid. Melting Point 150-153 ℃ (Decomposition)

NMR (DMSOd ₆ ) δ: 1.8-2.4 (2H, m), 2.9-3.4 (2H, m), 4.63 (1H, t, J = 7 Hz), 6.76 (1H, s), 6-7.6 (15H, m ), 7.85 (1 H, s), 8.70-7.6 (1 H, s).

(2) 10.5 of 30 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid and 60 ml of methanol It is added to 100 ml dioxane containing g of methyl L-phenylalanineate and the mixture is heated to 50 DEG C to dissolve the above-mentioned acid. 700 ml of dioxane is added to this solution and the mixture is stirred at room temperature for 5 hours.

The precipitate is recovered by filtration (filtrate is hereinafter referred to as "filtrate I") and the thus obtained 14.3 g of crude product is dissolved in 24 ml of methanol. 280 ml of dioxane is added to this methane ohm solution. The mixture was allowed to occlude for 4 hours at room temperature, and the crystal precipitate was collected by filtration (filtrate is hereinafter referred to as "filtrate II"). 12.2 g of (Z) -2- (2-tritylaminothiasome-4 -Yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (l-isomer) methyl L-phenylalanineate is obtained.

-14.0°(C=1, 메탄옴).

-14.0 ° (C = 1, methane).

12.2 g of the salt described above is dissolved in 120 ml of methanol and 176 ml of 0.1N hydrochloric acid is added thereto. The mixture is stirred for 2 hours under ice cooling. The precipitates are collected by filtration and washed with methanol.

7.5 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (l-isomer) are obtained. Another designation of this isomer is (Z) -2- (2-tritylaminothiasome-4-yl) -2-[((3S) -2-pyrrolidone-3-yl) oxyimino] acetic acid Denote. Melting point 142-143 ° C. (decomposition).

-38.8°(C=1, 디메틸포름아미드)

-38.8 ° (C = 1, dimethylformamide)

(3) The fruiting liquids I and II obtained in the above-mentioned (2) are concentrated to dryness under reduced pressure. The residue is dissolved in 250 ml of methane and then 450 ml of 0.1N hydrochloric acid is added dropwise to this solution. The mixture is stirred for 2 hours under ice cooling.

The precipitated crystal precipitate was collected by filtration, washed with metaohms and dried to obtain 20 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-). 3-yl) oxyimino] acetic acid (containing excess d-isomer) is obtained.

20.0 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid and 40 ml methanol were thus obtained. To 70 ml dioxane containing g of methyl D-phenylalanineate is added and the mixture is heated to 50 ° C. to dissolve the above-mentioned acid. 450 ml of dioxane is added to this solution.

Subsequently, the mixture is stirred at room temperature for 4 hours, and the crystal precipitate is collected by filtration. 13.3 g of the crude product thus obtained are dissolved in 20 ml of methanol and 260 ml of dioxane are added thereto.

The mixture is stirred for 4 hours at room temperature. The crystal precipitate was collected by filtration and 12.0 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (d- Isomer) methyl D-phenylalanineate is obtained.

+13.9°(C=1, 메탄옴).

+ 13.9 ° (C = 1, methane).

12.0 g of the salt described above is dissolved in 120 ml of methane and 174 ml of 0.1N hydrochloric acid is added thereto. The mixture is stirred for 2 hours under ice cooling. The precipitates are collected by filtration and washed with methane.

7.3 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid (d-isomer) are obtained. Another name for this preferential isomer is (Z) -2- (2-tritylaminothiasome-4-yl) -2-[((3R) -2-pyrrolidone-3-yl) oxyimino] acetic acid ( Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-pyrrolidone-3-yl) oxyimino] acetic acid. Melting point 143-144 ° C. (decomposition).

+37.4°(C=1, 디메틸포름아미드)

+ 37.4 ° (C = 1, dimethylformamide)

(4) 2.7 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-hydroxyiminoacetic acid was dissolved in 12 ml dimethylsulfoxide and added 1.0 in a nitrogen-visible environment. g of anhydrous potassium carbonate are added.

The mixture is stirred for 10 minutes at room temperature.

1.2 g of 1-methyl-3-bromo-2-pyrrolidone is added to this mixture and the mixture is stirred at room temperature for 5 hours. The reaction mixture is poured into 100 ml of water, and the crystal precipitate is collected by filtration. The crystals are dissolved in ethyl acetate, and the solution is washed with water and dried. The solution is concentrated under reduced pressure to remove the solvent.

The residue was then crystallized in isopropyl ether and filtered off to recover 2.1 g of ethyl (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(1-methyl-2-pi To give ralidone-3-yl) oxyimino] acetate.

NMR (CDCL ₃ ) δ: 1.30 (3H, t, J = 7 Hz), 2.0-2.7 (2H, m), 2.88 (3H, s), 3.0-3.6 (2H, m), 4.34 (2H, q, J = 7 Hz), 4.9 91 H, t, J = 7 Hz), 6.54 91 H, s), 6.87 (1 H, s) 7.0-7.5 (15 H, m).

2.7 g of ethyl (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-methyl-2-pyrrolidone-3-yl) oxyimino] acetate in 27 ml methanol Hang and add 4.9 ml of 2N sodium hydroxide solution. The mixture is heated to reflux for 20 minutes. After cooling, the mixture is concentrated under reduced pressure to remove methane.

The residue is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate.

The extract is dried and evaporated to remove the solvent under reduced pressure. The residue thus obtained was then crystallized in ether and recovered by filtration to obtain 2.15 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2-methyl-2-pyrrolidone). 3-yl) oxyimino] acetic acid is obtained. Melting point 142-145 ° C. (decomposition).

NMR (DMSO-d ₆ ) δ: 2.0-2.5 (2H, m), 2.77 (3H, s), 3.1-3.4 (2H, m), 4.78 (1H, t, J = 8 Hz), 6.87 (1H, s ), 6.9-7.5 (16H, m).

(5) 1.3 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-hydroxyiminoacetic acid was dissolved in 10 ml of dimethylformamide, followed by 0.24 g of sodium hydride ( 60% oil dispersion) is added. The mixture is stirred for 15 minutes at room temperature. 0.65 g of 3-bromo-2-piperidone is added to the mixture and the mixture is stirred at room temperature for 1.5 hours.

The reaction mixture is poured into water and washed with a mixture of ethyl acetate and tetrahydrofuran (1: 1).

The aqueous layer was adjusted to pH 3 with 10% hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran (1: 1). The extract is dried and concentrated to dryness under reduced pressure. Ether is then added to the residue and the resulting powder is recovered by filtration.

The powder (1.3 g) was purified by silica gel chromatography (solvent, methanol = 1: 4) to obtain 0.85 g of (Z) -2- (2-tritylaminothiasome-4-yl) -2-[(2- Piperedin-3-yl) acetic acid is obtained.

Melting point 145-150 ° C. (decomposition).

Claims (1)

Condensation reaction of a compound of formula (II) or a reaction derivative thereof with a compound of formula (III) or a salt thereof to afford a compound of formula (IV) and a protecting group therefrom to remove the protecting group 7β-[(Z) -2- (2-aminothiasome-4-yl) -2-oxyimino-acetamido] -3-cepem-4-carboxylic acid compound of (I) and its pharmaceutically Methods of preparing acceptable salts.

Wherein R ¹ is hydrogen or lower alkyl, R ² is (1-methyl-1H-tetrasome-5-yl) thio: R ³ is carboxy n is an integer of 2 or 3, or R ² is general expression

A group, R ³ is -COO- and, Y is hydrogen, hydroxymethyl or carboxylic night five days, n is the number 2 Protocol, R ⁴ represents a protecting group R ⁵ is R ² is (1-methyl-tetrahydro -1H- Zom-5-yl) thio is carboxy or protected carboxy and R ² is of the general formula

-COO- if the spirit is.